A clear understanding of the central control of respiratory function is a prerequisite for unraveling the mechanisms involved in many respiratory diseases. Activation of one or more reflexes has been used as one of the approaches for the identification of different respiratory neuronal pools, establish functional interconnections between them and identify neurotransmitters in these pathways. In this proposal, cardiopulmonary and carotid chemoreflexes will be activated and the following hypotheses tested: 1) Stimulation of the cardiopulmonary chemoreceptors induces cessation of phrenic nerve activity. This rapid and powerful response requires simultaneous involvement of the following pathways: (i) The neurons located in the nucleus tractus solitarius (nTS) are activated, these neurons, in turn, stimulate the neurons in the Botzinger-complex (BotC) and caudal ventral respiratory neuronal group (cVRG) via excitatory amino acid (EAA) receptors. Activation of BotC- and cVRG-neurons results in the release of gamma-aminobutyric acid (GABA) and/or glycine in the rostral ventral respiratory neuronal group (rVRG); (ii) The nTS also inhibits rVRG and pre-Botzinger complex (Pre- BotC), via direct GABAergic and/or glycinergic projections. The net effect of the activation of the afore-mentioned pathways is the inhibition of rVRG-neurons, which results in the cessation of phrenic nerve activity. 2) The stimulation of carotid chemoreceptors elicits an increase in phrenic nerve activity which is mediated via the following pathways: a projection from the chemoreceptor projection site, located in the commissural subnucleus of nTS, excites the rVRG-neurons which, in turn, excite the phrenic neurons. EAA receptors located in the rVRG and phrenic nucleus mediate the increase in phrenic nerve activity following the chemoreceptor-stimulation. The data generated from these investigations is likely to provide a better understanding of respirat ory regulatory mechanisms and will eventually help in devising better methods of treatment for many respiratory disorders.
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